UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, DC 20549

FORM 8-K

Current Report Pursuant

to Section 13 or 15(d) of the

Securities Exchange Act of 1934

Date of Report (Date of earliest event Reported): September 3, 2012

THERAVANCE, INC.

(Exact Name of Registrant as Specified in its Charter)

901 Gateway Boulevard
South San Francisco, California 94080
(650) 808-6000

(Addresses, including zip code, and telephone numbers, including area code, of principal executive offices)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

o            Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o            Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o            Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o            Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Item 8.01 Other Events.

On September 3, 2012 at the European Respiratory Society (ERS) Annual Congress 2012 in Vienna, Austria, GlaxoSmithKline (GSK) presented posters containing information from Phase 2 and Phase 3 studies of the combination treatment fluticasone furoate/vilanterol (FF/VI) and its component, FF, and from the Phase 2b study of umeclidinium bromide (UMEC). FF/VI, with proposed brand names of Relvar™ and Breo™, is an investigational once-daily inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) combination treatment for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD) and patients with asthma. UMEC, a long-acting muscarinic antagonist (LAMA), combined with VI, a LABA, is a once-daily investigational medicine for the maintenance treatment of patients with COPD. FF/VI and UMEC/VI are in development under the LABA collaboration agreement between GSK and the Theravance, Inc. (the “Company”). The Company also presented a poster containing information on a Phase 2a study of TD-4208, its internally-discovered investigational LAMA for the treatment of COPD. The posters are filed as Exhibits 99.1 to 99.16 to this report and are incorporated herein by reference.

Item 9.01 Financial Statements and Exhibits.

(d)   Exhibits

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SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

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EXHIBIT INDEX

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Exhibit 99.1

POSTER P2888

Efficacy of the novel inhaled corticosteroid, fluticasone furoate (FF)/long-acting beta2-agonist
vilanterol (VI) combination in reducing COPD exacerbations

Dransfield MT(1), Calverley PMA(2), Bourbeau J(3), Jones P(4), Hanania NA(5), Mahler DA(6), Vestbo J(7), Wachtel A(8), Martinez F(9), Barnhart F(10), Sanford L(11), Lettis S(11), Crim C(10)

(1)University of Alabama at Birmingham, Birmingham, AL, USA; (2)University of Liverpool, Liverpool, UK; (3)McGill University, Montreal, Canada; (4)St George’s University of London, London, UK; (5)Baylor College of Medicine, Houston, TX, USA; (6)Dartmouth Medical School, Hanover, NH, USA; (7)Manchester Academic Health Sciences Centre, Manchester, UK; (8)UCLA School of Medicine, Los Angeles, CA, USA; (9)University of Michigan, Ann Arbor, MI, USA; (10)Respiratory Medicine Development Center, GlaxoSmithKline, RTP, NC, USA; (11)Quantitative Sciences Division, GlaxoSmithKline, Uxbridge, UK

INTRODUCTION

·                  The combination of an inhaled corticosteroid (ICS) with a long-acting beta2 agonist (LABA) is an established treatment option for COPD patients experiencing acute exacerbations.(1)

·                  Exacerbation frequency is a key target for preventive treatment in COPD. Exacerbations are associated with accelerated deterioration and are a stronger predictor of adverse outcomes than percent predicted lung function.(1)

·                  FF and VI are, respectively, a novel ICS and LABA in development as a once-daily combination therapy (FF/VI) for COPD and asthma.

OBJECTIVES

·                  To assess the impact of addition of FF to VI on COPD exacerbations over one year, in patients with moderate-to-severe COPD. Safety endpoints are described separately (poster no. P2113).

METHODS

·                  Two phase III, multi-centre, randomised, double-blind, parallel-group studies (HZC871 and HZC970) identical in design, conduct and analysis.

·                  Patients (post-bronchodilator FEV1 <70%; FEV1/FVC ratio <70%; smoking history >10 pack years, having had >1 documented COPD exacerbation in the year prior to screening) completed a 4-week run-in period during which they received fluticasone propionate (FP)/salmeterol 250/50mcg twice-daily via DISKUS®/ ACCUHALERTM to determine adherence.

·                  Patients were randomised to receive FF/VI (50/25, 100/25, 200/25mcg) or VI (25mcg) once daily in the morning via a novel dry powder inhaler for 52 weeks.

RESULTS

Study population and demographics

·                  Pooled patient demographics and baseline characteristics are provided in Table 1.

·                  3255 patients were randomised and received at least one dose of study medication (ITT population); 2406 completed the studies.

·                  On-treatment withdrawal rates (FF/VI 50/25, 100/25, 200/25mcg, VI 25mcg) were, respectively: 25%, 25%, 25%, 29%.

·                  More patients in the VI group withdrew due to lack of efficacy, including exacerbations (VI 7% vs. FF/VI 3–4%).

Table 1. Patient demographics and baseline characteristics (pooled HZC871 & HZC970, ITT population)

Values are mean (SD) unless otherwise stated; ITT=intent-to-treat

Efficacy

·                  Relative to VI 25mcg, significant reductions in annual rate of on-treatment moderate/severe exacerbations* (primary endpoint) were seen with all strengths of FF/VI (Fig. 1)  

·                           mean (95% CI) rate reductions were: 16% (4, 27), 27% (16, 37) and 23% (12, 34) for FF/VI 50/25, 100/25, 200/25mcg, respectively.

·                  FF/VI 100/25mcg and 200/25mcg significantly reduced the risk (hazard ratio [HR] 0.75–0.76, p<0.001) for time to first on-treatment moderate/severe exacerbation (secondary endpoint) relative to VI 25mcg, however FF/VI 50/25mcg did not (HR 0.89, p=0.114) (Fig. 2).

·                  Significant reductions relative to VI were observed in the annual rate of on-treatment exacerbations requiring systemic or oral corticosteroids (secondary endpoint): 17% (1, 29), p=0.033; 30% (17, 41), p<0.001; 27% (14, 38), p<0.001 for FF/VI 50/25, 100/25, 200/25mcg, respectively.

*Moderate exacerbation: worsening of COPD symptoms requiring treatment with oral corticosteroids or antibiotics; severe exacerbation: worsening of COPD symptoms requiring hospitalisation

Figure 1. Annual rate ratios of on-treatment moderate/severe COPD exacerbations (pooled HZC871 & HZC970, ITT population)

Data comparisons vs. VI 25mcg; ratios calculated against moderate/severe exacerbation rates observed with VI in pooled analysis

·                  Trough (pre-dose) FEV1 at 52 weeks was significantly improved from baseline (secondary endpoint) relative to VI 25mcg: 38mL, 42mL, 46mL (p<0.001 for all comparisons) with FF/VI 50/25, 100/25, 200/25mcg, respectively (Fig. 3).

Figure 2. Kaplan-Meier plot of time to first on-treatment moderate/severe COPD exacerbation (pooled HZC871 & HZC970, ITT population)

Figure 3. Least squares mean (95% CI) change from baseline in trough FEV1 (pooled HZC871 & HZC970, ITT population)

LS=least squares; CI=confidence interval

CONCLUSIONS

·                  Addition of FF to VI significantly reduced the annual rate of moderate/severe exacerbations, annual rate of exacerbations requiring systemic/oral corticosteroids and, for the two higher strengths of FF/VI, the time to onset of first moderate/severe exacerbation. Additionally, a significant improvement in lung function was seen with FF/VI relative to VI.

·                  The 100/25mcg and 200/25mcg strengths of FF/VI conferred a consistent benefit over the study endpoints, whereas the 50/25mcg strength was not found to significantly delay time to first moderate/severe exacerbation.

·                  FF/VI has the potential to provide a once-daily preventive ICS/LABA option for COPD patients with a history of exacerbation.

REFERENCE

1. GOLD 2011. Available at: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_ Feb21.pdf [Last accessed 13 July 2012].

ACKNOWLEDGEMENTS

·                  The presenting author, M Dransfield, declares the following real or perceived conflicts of interest during the last 3 years in relation to this presentation: grant support from the National Heart, Lung, and Blood Institute; industry sponsored contracts from Boehringer Ingelheim, Boston Scientific, GlaxoSmithKline and Otsuka; consultancy for GlaxoSmithKline.

·                  These studies were funded by GlaxoSmithKline; GSK Study Codes HZC102871 & HZC102970, Clinicaltrials.gov NCT01009463 & NCT01017952.

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing, was provided by Ian Grieve at Gardiner-Caldwell Communications; this support was funded by GlaxoSmithKline.

Presented at the European Respiratory Society Annual Congress 2012 Vienna, Austria, 1–5 September, 2012

Exhibit 99.2

POSTER P2113

Safety of fluticasone furoate (FF), an inhaled corticosteroid in combination with vilanterol (VI), a long-acting beta agonist in management of COPD exacerbations

Calverley PMA(1), Dransfield MT(2), Bourbeau J(3), Jones P(4), Hanania NA(5), Mahler DA(6), Vestbo J(7), Wachtel A(8), Martinez F(9), Barnhart F(10), Sanford L(11), Lettis S(11), Crim C(10)

(1)University of Liverpool, Liverpool, UK; (2)University of Alabama at Birmingham, Birmingham, AL, USA; (3)McGill University, Montreal, Canada; (4)St George’s University of London, London, UK; (5)Baylor College of Medicine, Houston, TX, USA; (6)Dartmouth Medical School, Hanover, NH, USA; (7)Manchester Academic Health Sciences Centre, Manchester, UK; (8)UCLA School of Medicine, Los Angeles, CA, USA; (9)University of Michigan, Ann Arbor, MI, USA; (10)Respiratory Medicine Development Center, GlaxoSmithKline, RTP, NC, USA; (11)Quantitative Sciences Division, GlaxoSmithKline, Uxbridge, UK

INTRODUCTION

·                  The combination of inhaled corticosteroids (ICS) with a long-acting beta2 agonist (LABA) is an established treatment option for COPD patients who experience acute exacerbations.(1)

·                  FF and VI are, respectively, a novel ICS and LABA in development as a once-daily combination therapy (FF/VI) for COPD and asthma.

·                  Although the benefits of ICS in COPD are established, an association of ICS use with an increased risk of pneumonia(2) and bone disorders(3) has been reported.

OBJECTIVES

·                  To assess the safety and tolerability of three once-daily dosing regimens of FF/VI and one of VI in patients >40 years of age with moderate-to-severe COPD. Efficacy endpoints are described separately (poster no. P2888).

METHODS

·                  Two phase III, multi-centre, randomised, double-blind, parallel-group studies (HZC871 and HZC970) identical in design, conduct and analysis. Data from these studies were pooled.

·                  Patients (post-bronchodilator FEV1 <70%; FEV1/FVC ratio <70%; smoking history >10 pack years; having had >1 documented COPD exacerbation in the year prior to screening) completed a 4-week run-in period during which they received fluticasone propionate/salmeterol 250/50mcg twice daily via DISKUS™/ACCUHALER™ to determine adherence.

·                  Patients were randomised to receive one of the following, once daily in the morning via a novel dry powder inhaler for 52 weeks

·                  FF/VI 50/25mcg

·                  FF/VI 100/25mcg

·                  FF/VI 200/25mcg

·                  VI 25mcg.

RESULTS

Study population and demographics

·                  Pooled patient demographics and baseline characteristics are provided in Table 1.

·                  3255 patients were randomised and received at least one dose of study medication (ITT population); 2406 completed the studies.

Table 1. Patient demographics and baseline characteristics (pooled HZC871 & HZC970, ITT population)

Values are mean (SD) unless otherwise stated; ITT = intent-to-treat

·                  On-treatment withdrawal rates (FF/VI 50/25, 100/25, 200/25mcg, VI 25mcg) were, respectively: 25%, 25%, 25%, 29%. The incidence of withdrawal due to adverse events (AEs) was 7–8% in the FF/VI groups and 6% in the VI group.

Safety

·                  The most common on-treatment AEs were nasopharyngitis (14–19%), candidiasis (7–13%) and upper respiratory tract infection (9–11%) (Table 2).

·                  More patients receiving FF/VI (17–21%) than VI (14%) experienced AEs that were deemed treatment related by the investigator.

·                  Percent of patients with events in the Cardiac disorders system order class: VI 6%, FF/VI arms 4–5%.

·                  No fatal AEs were considered by the investigator to be treatment related.

·                  The incidence of local steroid effects and bone disorders, including fractures, was higher in patients receiving FF/VI than VI (Table 3). Bone fractures were the majority of events in the bone disorders category. The incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all FF/VI groups (2%) compared with the VI 25mcg group (<1%)

·                  the proportion of traumatic fractures was 75%, 73%, 68% and 38%, respectively for VI 25mcg, FF/VI 50/25, 100/25 and 200/25mcg. Fractures customarily associated with corticosteroid use (e.g. spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% across all treatment arms.

Table 2. Summary of AEs (pooled HZC871 & HZC970, ITT population)

Values are n (%) unless otherwise stated;

(a)3 patients had an event whilst on-treatment and an event post-treatment, both of which were recorded as leading to death; (b)candidiasis, oral candidiasis, oropharyngeal candidiasis and oesophageal candidiasis

Table 3. AE groupings of pre-defined special interest (pooled HZC871 & HZC970, ITT population)

(a) A hazard ratio less than unity favours VI

Safety (continued)

·                  Pneumonia occurred approximately twice as often in the FF/VI groups than in the VI group (Table 3).

·                  There were six cases of fatal pneumonia and one case of fatal COPD exacerbation with concurrent pneumonia in the FF/VI 200/25mcg group, all of which occurred in the HZC871 study and the majority of these cases were reported from one site; one case of fatal pneumonia occurred in the FF/VI 100/25 group of the HZC970 study

·                  the number of fatal cases was too small to allow investigation of risk factors for fatal pneumonia.

·                  No clinically relevant changes in clinical chemistry or haematology values, or in ECG-measured heart rate or QTcF, were observed.

CONCLUSIONS

·                  The use of FF/VI was associated with the expected increase in known steroid-associated AEs and bone disorders; correspondingly, the incidence of AEs and treatment-related AEs was higher in patients receiving FF/VI than VI.

·                  Overall rates of serious and fatal AEs were similar across the four treatment groups.

·                  The increase in risk of pneumonia with FF is consistent with the findings of previous studies of ICS in COPD.(2)

REFERENCES

(1)         GOLD 2011. Available at: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_ Feb21.pdf [Last accessed 26 June 2012].

(2)         Crim, C et al. Eur Respir J 2009;34:641–647.

(3)         Loke YC, et al. Thorax 2011;66:699-708

ACKNOWLEDGEMENTS

·                  The presenting author, PMA Calverley, declares the following real or perceived conflicts of interest during the last 3 years in relation to this presentation: received funds for advising the sponsors of this study on its conduct and analysis; performed similar functions with other pharmaceutical companies including AstraZeneca, Boehringer Ingelheim, Novartis, Nycomed and Takeda.

·                  These studies were funded by GlaxoSmithKline; GSK Study Codes HZC102871 & HZC102970, Clinicaltrials.gov NCT01009463 & NCT01017952.

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Ian Grieve at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Presented at the European Respiratory Society Annual Congress 2012 Vienna, Austria, 1–5 September, 2012

Exhibit 99.3

POSTER P2887

Lung function effects and safety of fluticasone furoate (FF)/vilanterol (VI) in patients with COPD: mid-high dose assessment

Martinez F(1), Boscia J(2), Feldman G(3), Scott-Wilson C(4), Kilbride S(5), Fabbri L(6), Calverley PMA(7), Crim C(4)

(1)University of Michigan, Ann Arbor, MI, USA; (2)CU Pharmaceutical Research, Union, SC, USA; (3)S. Carolina Pharmaceutical Research, Spartanburg, SC, USA; (4)GlaxoSmithKline, Research Triangle Park, NC, USA; (5)GlaxoSmithKline, London, UK; (6)University of Modena and Reggio Emilia Modena, Modena, Italy; (7)University of Liverpool, Liverpool, UK

INTRODUCTION

·                  There is increasing interest in once-daily dosing for respiratory medications; current inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combinations require twice-daily dosing, which may result in lower adherence and greater COPD costs.(1)

·                  FF/VI is a novel combination ICS/LABA that has been assessed in COPD at various strengths in small-scale studies.(2),(3)

OBJECTIVES

·                  To compare the efficacy and safety of two mid-to-high strengths of FF/VI with its constituent components, FF and VI, and placebo in patients with moderate-to-severe COPD.

METHODS

·                  Multi-centre, randomised, stratified (smoking status), placebo-controlled, double-blind, parallel-group study.

·                  Patients: age >40 years; history of moderate-to-severe COPD; smoking history >10 pack-years; post-bronchodilator (postBD) forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio <0.70; postBD FEV1 <0.70 predicted; score of >2 on the Modified Medical Research Council Dyspnoea Scale (mMRC).

·                  Following a 2-week single-blind placebo run-in, patients were randomised in a 1:1:1:1:1:1 ratio to receive one of six treatments taken once daily in the morning via novel dry powder inhaler for 24 weeks: FF 100mcg, FF 200mcg, VI 25mcg, FF/VI 100/25mcg, FF/VI 200/25mcg, or placebo

·                  Salbutamol (as needed) and ipratropium bromide alone (stable dose) were permitted for symptom relief during run-in and treatment periods.

RESULTS

Study population and demographics

·                  Of 1909 patients screened, 1224 formed the intent-to-treat (ITT) population, 924 of whom completed the study.

·                  Patient characteristics at baseline are outlined in Table 1.

·                  Patient-reported medication use prior to screening: short-acting beta2-agonists 62%, short-acting anticholinergics 34%, LABA 35%, ICS 24%.

Table 1. Descriptive characteristics of the study group (ITT population)

Values are mean (SD) unless otherwise stated

SD=standard deviation; BMI=body mass index; preBD=pre-bronchodilator; pred=predicted; postBD=post-bronchodilator; mMRC=Modified Medical Research Council Dyspnoea Scale

Efficacy: Co-Primary

·                  Weighted mean (wm; 0–4h post-dose, Day 168) and change from baseline in trough (23–24h post-dose, Day 169) FEV1 improved with all active therapies (Fig. 1a and b)

·                  wm and trough FEV1 significantly improved for VI 25mcg and FF/VI 200/25mcg vs. placebo; wm FEV1 significantly improved for FF/VI 200/25mcg vs. FF 200mcg; trough FEV1 was not significantly different for FF/VI 200/25mcg vs. VI 25mcg (Table 2)

·                  Significance for other comparisons could not be inferred due to the hierarchy employed in the statistical analysis.

Table 2. Primary and secondary study endpoint comparisons(a) (ITT population)

Values are differences in least square mean (95% CI);

*significant difference (p<0.001). (a)Log rank analysis was used to analyse the secondary endpoint of time to 100mL improvement on Day 1. Inference from the associated p-values could not be drawn due to the testing hierarchy employed; b = for regulatory purposes in the USA, CRQ-SAS is considered an ‘other’ endpoint.

Efficacy: Secondary

·                  Chronic Respiratory Questionnaire Self-Administered Standardized (CRQ-SAS) dyspnoea domain scores improved numerically for all comparisons except FF (either strength) vs. placebo; no comparisons achieved minimally clinically important difference (Table 2).

·                  Peak FEV1 (0–4h) on Day 1 numerically improved for all comparisons except FF/VI 200/25 vs. VI 25 (Table 2).

·                  Median (actual) time to onset (increase of 100mL above baseline in FEV1) on Day 1 was 16–17 min in the FF/VI and VI treatment groups, 231 and 242 min in the FF 200 and 100 groups, respectively and not determinable in the placebo group.

Figure 1. Lung function data over time for wmFEV1 (a) and trough FEV1 (b) (ITT population)

LS=least squares; CI=confidence interval

Safety

·                  Incidence of adverse events AEs and serious AEs (SAEs), were similar with active therapy vs. placebo (Table 3).

·                  Pneumonia events were low, <2% of subjects in FF-containing arms, <1% with VI 25 and 0 with placebo. No events were fatal.

·                  6 deaths were reported during the study; 5 on-treatment (1 each in the placebo, FF/VI 100/25 and 200/25 groups and 2 in the VI 25 group. None were considered treatment-related.

·                  Exacerbations occurred more frequently in the placebo arm (10%) vs. treatment arms (2–9%), and for VI (9%) vs. FF (2–5%).

·                  There were no clinically relevant abnormalities in clinical chemistry/haematology parameters, vital signs, 12-lead ECG and 24 h Holter monitoring.

·                  Assessment of 24 h urinary cortisol showed no clinically relevant or statistically significant effect of any treatment.

Table 3. Overview of AEs and SAEs (ITT population)

On-treatment and drug-related AEs occurring in >5% of patients in any treatment group are presented.

SOC=System Organ Class;* mutually exclusive coding

CONCLUSIONS

·                  The addition of the LABA VI to FF resulted in a rapid and sustained improvement in FEV1 in COPD patients with moderate-to-severe airflow obstruction.

·                  Once-daily FF/VI exhibited a tolerability profile that did not differ markedly from its individual components.

REFERENCES

(1)         Toy EL, et al. Respir Med 2011;105:435–441.

(2)         Lötvall J, et al. BMJ Open 2012;2:e000370.

(3)         Boscia JA, et al. Clin Ther 2012;12 July [Epub ahead of print].

ACKNOWLEDGEMENTS

·                  The presenting author, Fernando J Martinez, declares the following real or perceived conflicts of interest during the last 3 years in relation to this presentation: FJM has participated in advisory boards in COPD development for Actelion, Almirall, American Institutes for Research, Astra Zeneca, Bayer, BoomComm, Forest, GlaxoSmithKline, HCRC, Ikaria, IntraMed, Janssen, JK Associates, MedImmune, Merck, Merion, Novartis, Nycomed/Takeda, Pearl, Pfizer, Schering and Sudler and Hennessey. He has been a member of the steering committee for COPD studies sponsored by GlaxoSmithKline, Forest, MPex, and Nycomed/Takeda. He has participated in Food and Drug Administration mock panels for Boehringer Ingelheim and Forest. The University of Michigan received funds from Boehringer Ingelheim for a COPD study. He has served on speaker’s bureaus or in continuing medical education activities sponsored by American College of Chest Physicians, American Lung Association, Almirall, Astra Zeneca, William Beaumont Hospital, Boehringer Ingelheim, Center for Health Care Education, CME Incite, ePocrates, Forest, France Foundation, GlaxoSmithKline, Lovelace, MedEd, NACE, Nycomed, Potomac, Prescott, Sanofi Aventis, St Luke’s Hospital, and UpToDate. He has received royalties from Associates in Medical Marketing and Castle Connolly.

·                  This study was funded by GlaxoSmithKline; GSK Study Code HZC112207, Clinicaltrials.gov NCT01054885.

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Tom Gallagher at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Presented at the European Respiratory Society Annual Congress 2012 Vienna, Austria, 1–5 September, 2012

Exhibit 99.4

POSTER P2889

Efficacy of combination fluticasone furoate/vilanterol (FF/VI) and salmeterol/fluticasone propionate (SFC) over 12 weeks in patients with COPD

Agusti A(1), De Backer W(2), de Teresa L(3), Zvarich M(4), Locantore N(4), Barnes N(5), Bourbeau J(6), Crim C(4)

(1)Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, and CIBER Enfermedades Respiratorias (CIBERES), FISIB, Mallorca, Spain; (2)University of Antwerp, Antwerp, Belgium; (3)Clinica Mediterranea de Neurociencias, Alicante, Spain; (4)GlaxoSmithKline, Research Triangle Park, NC, USA; (5)Respiratory Medicine, Barts and The London NHS Trust, London, UK; (6)McGill University, Montreal, Quebec, Canada

INTRODUCTION

·             Currently available inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combinations require twice-daily dosing.

·             Fluticasone furoate/vilanterol (FF/VI) is a new once-daily ICS/LABA.

·             This is the first study to compare FF/VI with an established twice-daily ICS/LABA, fluticasone propionate (FP) and salmeterol (SAL) combination (SFC) in COPD.

OBJECTIVES

·             To compare the efficacy and safety profiles of once-daily FF/VI and twice-daily SFC in patients with moderate-to-severe COPD.

METHODS

·             Randomised, multi-centre, double-blind, double-dummy, parallel-group, comparative efficacy study.

·             Patients: >40 years of age with a clinical history compatible with COPD; diagnostic confirmation by post-bronchodilator FEV1/FVC ratio of <0.70; FEV1 <70% predicted; smoking history of >10 pack-years; moderate and/or severe COPD exacerbation within the last 3 years.

·             A sample size of 212 patients per group provided 90% power to detect a 60 mL difference between FF/VI and SFC in 24 h weighted mean (wm) FEV1 on Day 85 (primary endpoint)

·             median time-to-onset, defined as 100 mL FEV1 improvement over baseline on Day 1 and change from baseline in trough (pre-dose) FEV1 on Day 85 were secondary endpoints

·             the COPD-specific St George’s Respiratory Questionnaire (SGRQ Total) score and rescue-free 24 h periods were other endpoints.

·             Following a 2-week single blind placebo run-in, patients were randomised in a 1:1 ratio to receive the following study medication for 12 weeks

·             FF/VI 100/25mcg once daily in the morning via novel dry powder inhaler (nDPI) plus placebo twice daily (AM/PM) via DISKUSTM/ACCUHALERTM

·             SFC 50/500mcg twice daily (morning/evening) via DISKUSTM/ACCUHALERTM plus placebo once daily in the evening via nDPI.

·             Salbutamol was supplied to patients for symptomatic relief during run-in and treatment periods.

RESULTS

Study population and demographics

·             Baseline characteristics of study participants are outlined in Table 1.

·             Of 528 patients randomised (intent-to-treat [ITT] population), 489 completed the study.

·             Withdrawal rates were higher for FF/VI (9%) than for SFC (6%)

·             most frequent reasons were protocol deviations (FF/VI 3%, SFC 2%) and adverse events (AEs; FF/VI 2%, SFC 1%).

Table 1. Patient demographics and baseline characteristics (ITT population)

Values are mean (SD) unless otherwise stated; OD=once daily; BD=twice daily

Efficacy

·             There was a non-significant trend favouring FF/VI (130mL) vs. SFC (108mL) for weighted mean FEV1 after 12 weeks (D22mL [95% CI: –18, 63], p=0.282); the 24 h time course is illustrated in Fig. 1.

·             Median time to 100mL improvement from baseline was 16 min for FF/VI and 28 min for SFC (p=0.280).

·             Mean change from baseline in trough FEV1 on Day 85 was 111mL for FF/VI and 88mL for SFC (D23mL [95% CI: –20, 66], p=0.294).

·             A clinically meaningful improvement in SGRQ Total score was seen with FF/VI, but did not differ significantly from SFC (mean change –4.31 vs. –2.96, p=0.215).

·             Rescue-free 24 h periods were similar during Week 1 (FF/VI 61.6%, SFC 58.5%) and across Weeks 1–12 (FF/VI 62.5%, SFC 59.8%).

Figure 1. 0–24h LS mean change from baseline (mL) on day 84 (ITT population)

FEV1 measurements were collected at 5, 15, 30 and 60 min, and 2, 4, 6, 8, 12, 13, 14, 16, 20 and 24 h on Day 84; LS=least squares

Safety

·             On-treatment AEs are summarised in Table 2.

·             On-treatment AEs, treatment-related AEs and serious AEs (SAEs) were similar for FF/VI and SFC

·               no SAEs were considered treatment related by the investigator

·             there were no fatal on-treatment AEs; one fatal event during the post-treatment period (congestive heart failure) was not considered treatment related.

·             Cardiovascular AEs were more frequent in the FF/VI group; local steroid effects were more frequent in the SFC group.

Table 2. Summary of on-treatment AEs by treatment group (ITT population)

·             Exacerbation frequency: FF/VI 2%, SFC 3%; all exacerbations resolved during the study period.

·             There were few reports of pneumonia in both treatment groups (FF/VI: 1 patient, SFC: 2 patients).

·             There were no apparent treatment-related changes in clinical laboratory parameters, ECGs or vital signs.

CONCLUSION

·             Once-daily FF/VI and twice-daily SFC improved lung function and health status similarly in patients with moderate-to-severe COPD without substantial safety concerns.

ACKNOWLEDGEMENTS

·             The presenting author, J Bourbeau, declares the following real or perceived conflicts of interest during the last 3 years in relation to this presentation: participation on medical advisory boards, continuing health education activities and/or clinical research trials for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, Merck, Novartis, Pfizer and Takeda.

·             This study was funded by GlaxoSmithKline; GSK Study Code HZC113107, Clinicaltrials.gov NCT01342913.

·             Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Tom Gallagher at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Presented at the European Respiratory Society Annual Congress 2012 Vienna, Austria, 1–5 September, 2012

Exhibit 99.5

POSTER P1788

Effect of fluticasone furoate (FF)/vilanterol (VI) once daily on risk of severe exacerbations in asthma

Bateman ED(1), O’Byrne PM(2), Busse WW(3), Lötvall J(4), Bleecker ER(5), Andersen L(6), Frith L(7), Lim J(7), Jacques L(8), Woodcock A(9)

(1)Department of Medicine, University of Cape Town, Cape Town, South Africa; (2)Michael G DeGroote School of Medicine, McMaster University, Hamilton, Canada; (3)Department of Medicine, University of Wisconsin, Madison, WI, USA; (4)Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden; (5)Center for Genomics and Personalized Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA; (6)Respiratory Medicines Development Centre, GlaxoSmithKline, Research Triangle Park, NC, USA; (7)Quantitative Sciences Division, GlaxoSmithKline, London, UK; (8)Respiratory Medicines Development Centre, GlaxoSmithKline, Uxbridge, UK; (9)School of Translational Medicine, University of Manchester, Manchester, UK

INTRODUCTION

·                  The addition of LABA to ICS in twice-daily combination regimens has been shown to significantly improve pulmonary function and reduce the risk of exacerbations relative to ICS alone.(1),(2)

·                  FF and VI are, respectively, a novel ICS and LABA in development for once-daily combination therapy in asthma and COPD.

OBJECTIVES

·                  To assess the risk of severe asthma exacerbations with once-daily FF/VI 100/25mcg compared with once-daily FF 100mcg in patients >12 years of age with asthma uncontrolled on ICS.

METHODS

·                  Phase III, randomised, multi-centre, double-blind, parallel-group study of variable duration (>24–76 weeks).

·                  End of study was when 330 patients experienced an on-treatment severe asthma exacerbation

·             a deterioration of asthma requiring use of systemic corticosteroids for >3 days or inpatient hospitalisation or emergency room visit due to asthma, with use of systemic corticosteroids.(3)

·                  Eligible patients had history of asthma for >1yr prior to screening and >1 asthma exacerbation requiring systemic corticosteroids and/or hospital/emergency room visit in the previous year.

·                  Patients received one of the following treatments for a minimum of 24 weeks up to 76 weeks after a 2-week run-in period

·             FF/VI 100/25mcg once daily in the evening via novel dry powder inhaler (nDPI)

·             FF 100mcg once-daily in the evening via nDPI.

·                  An interim analysis for safety and efficacy was carried out by an independent data monitoring committee, after around half of the designated number of patients experienced an on-treatment severe asthma exacerbation.

RESULTS

Study population and demographics (Table 1)

·                  Of 2668 patients screened, 2020 were randomised, 2019 received at least one dose of study medication (intent-to-treat [ITT] population) and 1748 completed the study (FF/VI: 88%; FF: 85%).

Table 1. Patient demographics and baseline characteristics (ITT population)

Values are mean (SD) unless otherwise stated

·                  583 (58%) of patients in the FF/VI group and 567 (56%) in the FF group received study treatment for >52 weeks.

Efficacy

·                  The time to first severe asthma exacerbation (primary endpoint) was significantly delayed with FF/VI vs. FF (hazard ratio [HR] 0.795 [95% CI: 0.642, 0.985]; interim adjusted p=0.036); a 20% risk reduction (Fig. 1).

·                  Annualised rate of severe asthma exacerbations (secondary endpoint) was significantly lower with FF/VI (0.14/yr) vs. FF (0.19/yr) (p=0.014); a 25% (95% CI: 5, 40) rate reduction.

Figure 1. Time to first severe asthma exacerbation, cumulative incidence (ITT population)

CI = confidence interval

Note: Cox Proportional Hazards Model with covariates of baseline disease severity (baseline FEV1), sex, age, region, and treatment

·                  186 (18%) of patients receiving FF experienced >1 severe asthma exacerbation during the treatment period compared with 154 (15%) receiving FF/VI. Total exacerbations: FF/VI 200, FF 271.

·                  Mean change from baseline in trough FEV1 (secondary endpoint) was significantly greater with FF/VI (ANCOVA p<0.001). Output of a repeated measures analysis of change from baseline in trough FEV1 is shown in Fig. 2.

Figure 2. Repeated measures analysis of change from baseline in trough FEV1 (ITT population)

LS = least squares; CI = confidence interval

Note: Each patient’s final FEV1 measurement (taken at the Week 76/end of study visit) was re-labelled according to that patient’s duration on treatment

Safety

·                  Incidence of AEs was similar between treatment groups (Table 2).

·                  AEs deemed treatment related: 7% both groups.

·                  Withdrawal due to AEs: 2% both groups.

·                  Incidence of serious AEs: FF/VI 4%, FF 3%. One SAE (tachyarrhythmia) in the FF/VI group and three (pleurisy, asthma, non-cardiac chest pain) in the FF group were deemed potentially treatment-related by the investigator.

·                  Three fatal AEs occurred: pneumonia, on-treatment (FF group), road traffic accident, on-treatment (FF/VI group), and metastatic lung cancer, post-treatment (FF group); none were deemed to be related to treatment or asthma.

·                  The proportion of patients hospitalised due to severe asthma exacerbations was low in both treatment groups (<1%).

Table 2. On-treatment AEs occurring in >5% of patients in either treatment group (ITT population)

CONCLUSIONS

·                  The addition of VI to FF significantly reduced the risk of severe asthma exacerbations in a population uncontrolled on ICS and with a recent history of >1 exacerbations.

·                  The overall frequency of severe asthma exacerbations in both treatment groups was low compared with those seen in other studies of ICS with or without LABA.

·                  FF/VI improved lung function, as measured by trough FEV1, relative to FF and had a similar safety profile with no increased risk of serious asthma-related events.

REFERENCES

(1) O’Byrne PM, et al. Chest 2008;134:1192–9.

(2) Shapiro G, et al. Am J Respir Crit Care Med 2000;16:527–34.

(3) Reddel HK, et al. Am J Respir Crit Care Med 2009;180:59–99.

ACKNOWLEDGEMENTS

·                  The presenting author, ED Bateman, declares the following real or perceived statements of interest during the last 3 years in relation to this presentation: EDB has received remuneration from GlaxoSmithKline for consulting, participation in advisory boards, and lectures. His institution has received funds for participation as a centre in clinical trials sponsored by GlaxoSmithKline.

·                  This study was funded by GlaxoSmithKline; GSK Study Code HZA106837, ClinicalTrials.gov NCT01086384.

·                  Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Ian Grieve at Gardiner-Caldwell Communications and was funded by GlaxoSmithKline.

Presented at the European Respiratory Society Annual Congress 2012 Vienna, Austria, 1–5 September, 2012

Exhibit 99.6

POSTER P1794

Efficacy and safety of fluticasone furoate/vilanterol (FF/VI) once-daily for 24 weeks in persistent asthma

O’Byrne PM(1), Bleecker ER(2), Bateman ED(3), Busse WW(4), Woodcock A(5), Forth R(6), Toler T(7), Jacques L(8), Lötvall J(9)

(1)Michael G DeGroote School of Medicine, Hamilton, Ontario, Canada; (2)Center for Genomics and Personalized Medicine, Wake Forest University Health Sciences Winston-Salem, NC, USA; (3)Department of Medicine, University of Cape Town, Cape Town, South Africa; (4)Department of Medicine, University of Wisconsin, Madison, WI, USA; (5)School of Translational Medicine, University of Manchester, Manchester, UK; (6)Quantitative Sciences Division, GlaxoSmithKline, RTP, NC, USA; (7)Respiratory Medicines Development Center, GlaxoSmithKline, RTP, NC, USA; (8)Respiratory Medicines Development Centre, GlaxoSmithKline, London, UK; (9)Krefting Research Centre, University of Gothenburg, Sweden

INTRODUCTION

·                  Inhaled corticosteroids (ICS) are considered the most effective anti-inflammatory treatments for all severities of persistent asthma.(1)

·                  Adding a long-acting beta2 agonist (LABA) to an ICS improves asthma control and reduces exacerbation frequency.(2)

·                  FF and VI are, respectively, a novel ICS and LABA in development as a combined (FF/VI) once-daily therapy for asthma and COPD.

OBJECTIVES

·                  To compare the efficacy and safety of once-daily FF/VI with once-daily FF and twice-daily fluticasone propionate (FP) in patients >12 years of age with moderate-to-severe persistent asthma.

·                  To demonstrate non-inferiority of once-daily FF 200mcg vs. twice-daily FP 500mcg in trough FEV1, using a non-inferiority margin of 125mL.

METHODS

·                  Phase III, randomised, multi-centre, double-blind, double-dummy, parallel-group study.

·                  Patients: asthma for >12 weeks; documented use of ICS (with/without LABA) for >12 weeks with stable ICS dose (FP 500mcg twice daily (or equivalent) or mid-dose ICS/LABA) for >4 weeks; pre-bronchodilator FEV1 40–90% predicted.

·                  Following a 4-week run-in, patients were randomised (1:1:1) to receive one of the following for 24 weeks

·                  FF/VI 200/25mcg once daily (evening dosing) via novel dry powder inhaler (nDPI)

·                  FF 200mcg once daily (evening dosing) via nDPI

·                  FP 500mcg twice daily (morning/evening dosing) via DISKUSTM/ACCUHALERTM.

RESULTS

Study population and demographics (Table 1)

·                  Of 1206 patients screened, 586 were randomised and dosed (intent-to-treat [ITT] population) and 476 completed the study.

Table 1. Patient demographics and baseline characteristics (ITT population)

Values are mean (SD) unless otherwise stated

Efficacy

·                  FF/VI demonstrated benefit over FF and FP in mean change from baseline in trough (pre-bronchodilator, pre-dose) FEV1 at Week 24 (co-primary endpoint; ANCOVA analysis; last observation carried forward): 394mL FF/VI; 201mL FF; 183mL FP

·                  treatment differences (95% CI): FF/VI vs. FF 193mL (108, 277); FF/VI vs. FP 210mL (127, 294) (both p<0.001)

·                  FF 200mcg was non-inferior to FP 500mcg: treatment difference 18mL (–66mL, 102mL)

·                  repeated measures analysis was consistent (Fig. 1).

·                  FF/VI demonstrated benefit over FF and FP in weighted mean 0–24h post-dose serial FEV1 after 24 weeks (co-primary endpoint; ANCOVA analysis): 2.668L FF/VI; 2.532L FF; 2.462L FP

·                  treatment differences (95% CI): FF/VI vs. FF 136mL (1, 270; p=0.048); FF/VI vs. FP 206mL (73, 339; p=0.003)

·                  individual serial FEV1 assessments are shown in Fig. 2.

·                  There were significantly more % rescue-free 24-h periods (powered secondary endpoint) (11.7 [p<0.001], equivalent to 0.8 per week) and % symptom-free 24-h periods (secondary endpoint) (8.4 [p=0.01], 0.6 per week) compared with baseline for FF/VI vs. FF.

·                  No statistical difference between FF/VI and FF in Total Asthma Quality of Life Questionnaire score at either Weeks 12 or 24 (secondary endpoint).

Figure 1. Repeated measures analysis of change from baseline in trough FEV1 over 24 weeks (ITT population)